Alcohol abuse and alcoholism are widespread public health problems that are associated with debilitating medical, social, and psychological consequences. The opioid antagonist naltrexone is approved for the treatment of alcohol dependence; however, naltrexone is not universally effective in all people. Recent evidence suggests that a N40D (A188G) single nucleotide polymorphism (SNP) in the human mu opioid receptor gene may contribute to individual variation in sensitivity to the behavioral effects of alcohol, as well as to subsequent responsiveness to naltrexone therapy. Rhesus monkeys also have a SNP (P26R, C77G) that appears to have many of the same functional, physiological and behavioral consequences as the human SNP. Using state-of-the-art genotyping techniques and in vitro assays, allelic variants of the rhesus monkey mu opioid receptor that alter protein structure and/or function or affect subsequent gene expression levels will be systematically identified and characterized (Specific Aim 1). In addition, the role of mu opioid receptor haplotypes in individual sensitivity to the reinforcing and relapse-inducing effects of alcohol will be explored in rhesus monkeys that have been selected a priori on the basis of their mu opioid receptor P26R genotype and have been trained to orally self-administer alcohol (Specific Aim 2). Finally, the role of mu opioid receptor haplotypes in individual responsiveness to the ability of naltrexone to reduce oral alcohol self-administration and diminish alcohol priming-induced reinstatement will be investigated in rhesus monkeys that have been selected a priori on the basis of their mu opioid receptor P26R genotype and have been trained to orally self- administer alcohol (Specific Aim 3). Integration of results from the three specific aims will yield needed information about how specific genetic variables may play a role in vulnerability to the addictive effects of alcohol. Ultimately, the results should allow for a more informed selection of anti-alcohol medication that is tailored to an individual's likelihood of positive treatment outcome. PUBLIC HEALTH RELEVANCE: Alcohol use disorders are widespread public health problems that are associated with debilitating medical, social, and psychological consequences and for which no universally effective treatment medication is available. Our studies will yield key information about how specific genetic variables may play a role in vulnerability to the addictive effects of alcohol. Ultimately, our results should allow for a more informed selection of anti-alcohol medication that is tailored to an individual's likelihood of positive treatment response.